強(qiáng)直性脊柱炎（AS）作為一種以脊柱附著點(diǎn)炎癥和骨融合為特征的慢性炎癥性關(guān)節(jié)炎，其治療長期依賴腫瘤壞死因子抑制劑（TNFi）。然而，臨床中 30%-40% 的 AS 患者對(duì) TNFi 治療無響應(yīng)，且現(xiàn)有炎癥標(biāo)志物（如 CRP）和臨床特征（如年齡、病程）對(duì)治療響應(yīng)的預(yù)測價(jià)值有限，未能實(shí)現(xiàn)精準(zhǔn)分層治療。闡明 TNFi 耐藥的免疫學(xué)機(jī)制并篩選可靠預(yù)測生物標(biāo)志物，成為改善 AS 治療結(jié)局的關(guān)鍵問題。

2025 年 7 月，來自韓國先進(jìn)科學(xué)技術(shù)研究院（KAIST）、首爾國立大學(xué)醫(yī)學(xué)院等機(jī)構(gòu)的研究團(tuán)隊(duì)在《Nature Communications》雜志發(fā)表研究論文 “Type 1 interferon signature and allograft inflammatory factor-1 contribute to refractoriness to TNF inhibition in ankylosing spondylitis”。該研究揭示了強(qiáng)直性脊柱炎（AS）患者對(duì)腫瘤壞死因子抑制劑（TNFi）治療耐藥的關(guān)鍵機(jī)制，并發(fā)現(xiàn)了可預(yù)測治療反應(yīng)的生物標(biāo)志物。

該研究圍繞 TNFi 治療響應(yīng)差異的核心問題，采用縱向多組學(xué)聯(lián)合單細(xì)胞解析策略。研究納入接受 TNFi 治療的 AS 患者隊(duì)列（含 1 個(gè)發(fā)現(xiàn)隊(duì)列和 3 個(gè)驗(yàn)證隊(duì)列），通過單細(xì)胞 RNA 測序對(duì)治療前后的外周血單核細(xì)胞（PBMCs）進(jìn)行免疫景觀分析，結(jié)合 UMAP 聚類、Milo 差異豐度分析等生物信息學(xué)方法，解析應(yīng)答者與非應(yīng)答者的細(xì)胞亞群和轉(zhuǎn)錄組差異。同時(shí)，通過體外細(xì)胞實(shí)驗(yàn)（AIF-1 刺激、siRNA 敲除）驗(yàn)證關(guān)鍵分子功能，并利用 ELISA、qRT-PCR 等技術(shù)在多隊(duì)列中驗(yàn)證生物標(biāo)志物效能。

研究發(fā)現(xiàn)，非應(yīng)答者基線時(shí)即存在顯著升高的 I 型干擾素（IFN）信號(hào)，該信號(hào)與 TNFi 治療后反常增強(qiáng)的 IFN 應(yīng)答和 Th17 細(xì)胞反應(yīng)密切相關(guān)。進(jìn)一步分析鑒定出同種異體移植炎癥因子 - 1（AIF-1）為核心生物標(biāo)志物：非應(yīng)答者基線血清 AIF-1 水平顯著升高，且與 I 型 IFN 信號(hào)強(qiáng)度正相關(guān)，以 63.5 pg/ml 為臨界值時(shí)，預(yù)測非響應(yīng)的敏感性達(dá) 89.5%、特異性 82.1%。機(jī)制上，AIF-1 通過上調(diào) IFNα 受體表達(dá)和促進(jìn) IL-1β、IL-6 等細(xì)胞因子分泌，增強(qiáng) Th17 細(xì)胞分化，形成炎癥放大循環(huán)。單細(xì)胞分析顯示，非應(yīng)答者基線 CXCL10?經(jīng)典單核細(xì)胞和 ISG?非經(jīng)典單核細(xì)胞比例更高，TNFi 治療后這些亞群的炎癥特征進(jìn)一步強(qiáng)化。

當(dāng)前 AS 研究多聚焦 TNF 通路調(diào)控，對(duì)治療耐藥的免疫異質(zhì)性解析不足，且缺乏穩(wěn)定可靠的預(yù)測標(biāo)志物。該研究首次揭示 I 型 IFN 信號(hào)和 AIF-1 在 TNFi 耐藥中的核心作用，通過單細(xì)胞技術(shù)精準(zhǔn)定位關(guān)鍵單核細(xì)胞亞群，結(jié)合多隊(duì)列驗(yàn)證確立 AIF-1 的臨床預(yù)測價(jià)值，為 AS 的個(gè)性化治療提供了從機(jī)制到應(yīng)用的完整證據(jù)鏈，填補(bǔ)了現(xiàn)有生物標(biāo)志物臨床轉(zhuǎn)化的空白。

產(chǎn)品編號(hào)：RPC288Hu01

產(chǎn)品名稱：離子化鈣結(jié)合適配分子1(AIF1)重組蛋白

a Schematic of the experimental design. PBMCs from healthy donors (n?=?4) were treated with AIF-1 or control (Ctl) and subjected to scRNA-seq. In addition, CD14+ monocytes were isolated from PBMCs using CD14 Microbeads and treated with AIF-1 or Ctl, followed by bulk RNA sequencing. Created in BioRender. https://BioRender.com/q70l192. b UMAP of monocytes from AIF-1-treated PBMCs, revealing 10 clusters (n?=?2245). c Dot plot showing the average expression of key markers in each cluster from AIF-1-treated UMAP. d Violin plot of log-normalized expression values for SLAMF7, GBP1, IRF7, and ISG20. e Bar plots showing the proportion of each cluster in AIF-1-treated versus Ctl PBMCs, represented as the AIF-1/Ctl ratio. f Dot plot comparing the expression of IFNAR1 and IFNGR1 between AIF-1 treated monocytes and control monocytes. The accompanying table summarizes the average log2 fold change (avg_log2FC), Bonferroni-adjusted p-value (adj p-value), and expression levels (exp) in AIF-1 treated versus control cells. (Wilcoxon rank sum test, two-sided). g Heatmap showing the expression of inflammatory cytokines (e.g., IL1B, IL6, IL-23) in monocytes treated with AIF-1 versus Ctl as determined by bulk RNA sequencing. h GSEA plot of DEGs from bulk RNA-seq, highlighting monocyte-derived dendritic cells (Mo-DCs) and BDCA1+ DC markers